HUMAN BIOCHEMICAL GENETICS

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1.Seventy-five cystinosis patients are seen in the Human Genetics Branch and most are treated with cysteamine or phosphocysteamine. In pre- transplant patients, cysteamine therapy is maintaining renal function and assisting growth. In post-transplant patients, complications of long-term cystine accumulation are described. These include myopathy, neurological involvement, and severe swallowing difficulties. Cysteamine eyedrops (0.5%) dissolve corneal cystine crystals in young children and remove the haziness from the eyes of older children, with relief of photophobia. 2.Impaired lysosomal egress of free sialic acid has been demonstrated as the basic defect in Infantile Free Sialic Acid Storage Disease (ISSD). ISSD fibroblasts also store glucuronic acid due to impaired egress out of the lysosome. 3.The basic defect in sialuria has been demonstrated to be impaired feedback inhibition by CMP sialic acid of UDP N-acetylglucosamine 2-epimerase. Cytosolic free sialic acid levels can be reduced by treatment of the fibroblasts with cytidine. 4.The human kidney filters but does not reabsorb free sialic acid. This was demonstrated by studying patients with different filtered loads of free sialic acid. 5.Copper metabolism is impaired in Menkes' disease and Indian Childhood Cirrhosis cells. A 23 Kd protein with copper-binding activity is being characterized using normal human fibroblasts. Copper histidinate therapy of Menkes' disease is being pursued by a clinical protocol. 6.Unknown lysosomal storage disorders are investigated by carbohydrate analysis performed by pulsed ampermetric detection, and by lipid analysis performed by HPLC separation and Varex analysis. 7.Lysosomal membrane carriers are being investigated by reconstitution of proteoliposomes to be used as a test system for functional transport.